We have identified a novel basic leucine zipper (bZIP) protein, designated ATF-7, that physically interacts with the PRL-1 protein-tyrosine phosphatase (PTPase). PRL-1 is a predominantly nuclear, farnesylated PTPase that has been linked to the control of cellular growth and differentiation. This interaction was initially found using the yeast two-hybrid system. ATF-7 is most closely related to members of the ATF/CREB family of bZIP proteins, with highest homology to ATF-4. ATF-7 homodimers can bind specifically to CRE elements. ATF-7 is expressed in a number of different tissues and is expressed in association with differentiation in the Caco-2 cell model of intestinal differentiation. We have confirmed the PRL-1⅐ATF-7 interaction and mapped the regions of ATF-7 and PRL-1 important for interaction to ATF-7's bZIP region and PRL-1's phosphatase domain. Finally, we have determined that PRL-1 is able to dephosphorylate ATF-7 in vitro. Further insight into ATF-7's precise cellular roles, transcriptional function, and downstream targets are likely be of importance in understanding the mechanisms underlying the complex processes of maintenance, differentiation, and turnover of epithelial tissues.

Mechanisms controlling the tyrosine phosphorylation of cellular proteins are important in the regulation of cellular processes including growth and differentiation. It has become clear that a number of protein tyrosine phosphatases (PTPases) that dephosphorylate tyrosyl residues may play a role in the growth response, both in growth-promoting and growth-inhibiting capacities. We identified PRL-1, a unique nuclear PTPase that is an immediate-early gene in liver regeneration and is positively associated with growth, including fetal and neoplastic hepatic growth and anchorage-independent growth after overexpression in fibroblasts. In this study, we show that PRL-1 nuclear protein levels in regenerating liver parallel those of its mRNA, although the peak occurs later, just before the onset of DNA synthesis. We further show that PRL-1 is significantly expressed in intestinal epithelia and that, in contrast to the expression pattern of PRL-1 in liver, its expression is associated with cellular differentiation in intestine. Specifically, PRL-1 is expressed in villus but not crypt enterocytes and in confluent differentiated but not undifferentiated proliferating Caco-2 colon carcinoma cells. The expression of PRL-1 in intestine shows inverse correlation with proliferating cell nuclear antigen expression, a marker for S-phase cells. These results suggest that PRL-1 may play different roles in these two digestive tissues. Such a dichotomy of roles has previously been described for some protein tyrosine kinases and might be due to the availability of alternate substrates in different tissues.

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